Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

• n is an integer of from 3 to 5
• m is O or an integer of l or 2
• R is methyl or methoxy and pharmaceutically acceptable salts of the compounds of the said formula.
• the compounds are stated to have a depressant action on the central nervous system.
• n is an integer from 3 to 5 inclusive
• R is selected from the group consisting of hydroxy, amino, dimethylamino and OR wherein R is selected from the group consisting of acetyl, propionyl, butyryl, carbamoyl, methylcarbamoyl and dimethylcarbamoyl; and pharmaceutically acceptable salts thereof.
• the invention also provides therapeutic compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
• the compounds of the invention are potent inhibitors of acetylcholinesterase and may be expected to be of use in clinical situations which are attributable to an effective lack of the neurotransmitter. acetylcholine.
• the compounds of Formula I in which R is a hydroxy group may be prepared from the corresponding methyl ethers in which R is a methoxy group, by treatment with reagents commonly employed for the cleavage of ethers, such as hydrobromic acid and boron tribromide.
• the said methyl ethers may be prepared by the reaction of a ketone of the formula:
• n is aninteger of 3 to 5 and R is a methoxy III wherein n is an integer of 3 to 5, R is a dimethylamino group, with pyrrolidine in the presence of formic acid,
• the compounds of Formula I in which-R is an amino group may be prepared from the compounds of Formula I in which R is a hydroxy group by reaction with diethyl phosphorochloridate to afford a diethyl phosphate ester which is converted to a primary amine by.
• a sample was characterised by treatment with iodomethane as the methiodide m.p. 166 to 167C.
• a sample was characterised by treatment with iodomethane as the methiodide m.p. 184 to 186C.
• Compounds that are potent inhibitors of acetylcholinesterase may be expected to be of use in clinical situations where the pathological conditions are characterised by a lack of either skeletal or smooth muscle tone,
• myasthenia gravis e.g., myasthenia gravis, paralytic ileus, urinary reten-' tion and glaucoma. Theymay also be used in the reversal of muscle relaxation induced during surgery by nondepolarising skeletal muscle relaxants such as D- tubocurarine.
• Myasthenia is a syndrome of increased fatiguability in striated muscle.
• the characteristic feature from which the disease derives its name is a severe weakness of voluntary muscles which begins after exercise but which may disappear after a short rest. Although the weakness may affect any muscle, the eyelids, extraocular muscles, bulbar muscles, neck and proximal muscles of the upper limbs are most commonly involved. The hand, lower limb and trunk muscles are usually involved later.
• acetylcholine is the neurotransmitter at the neuromuscular junction. In myasthenia there appears to be a disturbance in the release of acetylcholine from the nerve ending resulting in impaired neuromuscular transmission. The symptoms which appear as a result of this defect may be treated by blocking acetylcholinesterase, the enzyme normally responsible for the metabolism of acetylcholine.
• Anticholinesterase tests may be subdivided into in vitro and in vivo tests.
• cis-2-(3- hydroxyphenyl 1 -pyrrolidinocyclohexane is more potent than 3 commercial drugs but is less potent than neostigmine.
• the compound has a longer duration of action which may offer advantage in the treatment of myasthenia.
• the likely oral dose is 40 to 60 mg.
• this compound is a tertiary amine it should be both regularly and completely absorbed after oral administration. This is in contrast to established antiacetylcholinesterases which are poorly and irregularly absorbed after oral dosage due to their quaternary nature.
• compositions may be in a form suitable for oral administration and may take the form of capsules, tablets, granules or liquid preparations such as elixirs, syrups or suspensions.
• the compositions are advantageously employed in a unit dosage form.
• the unit dosage form contains from 20 mg to mg, of the compound of said formula. 3
• n is an integer from 3 to inclusive
• R is selected from the group consisting of hydroxy, amino, dimethylamino and OR wherein R is selected from the group consisting of acetyl, propionyl, butyryl, carbamoyl, methylcarbamoyl and dimethylcarbamoyl; and pharmaceutically acceptable salts thereof 2.
• a compound as claimed in claim 1 which is cis-2- (3-hydroxyphenyl l -pyrrolidinocyclohexane.
• a compound as claimed in claim 1 which is cis-2- 3-butyryloxyphen yl l -pyrrolidinocyclohexane.
• n isan integer of 3 to 5 and R is a methoxy group, with hydrob romic acid or boron tribromide.
• a process for the preparation of a compound of formula I as claimed in claim 1 wherein R is an amino group which process comprises reacting the corresponding compound of formula I wherein R is a by droxy group with diethyl phosphorochloridate to form a diethyl phosphate ester which is converted to a primary amine by reaction with potassamide and potassium in liquid ammonia.
• a process for the preparation of a compound of formula] as claimed in claim 1 wherein R is a dimethylamino group which process comprises reacting a ketone of formula III wherein n is an integer of 3 to 5 and R is a dimethylamino group, with pyrrolidine in the presence of formic acid.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (1)

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• 1972
  • 1972-06-07 GB GB2660272A patent/GB1395235A/en not_active Expired
• 1973
  • 1973-05-30 ZA ZA733687A patent/ZA733687B/xx unknown
  • 1973-05-30 AU AU56268/73A patent/AU5626873A/en not_active Expired
  • 1973-06-04 US US366609A patent/US3899510A/en not_active Expired - Lifetime
  • 1973-06-06 FR FR7320644A patent/FR2187296B1/fr not_active Expired

Patent Citations (1)

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